<![CDATA[Methotrexate is the recommended first-line conventional disease-modifying antirheumatic drug for rheumatoid arthritis; interindividual variability in treatment response and toxicity remains a major clinical challenge. Pharmacogenomics provides a biological basis for this variability, yet reported associations between genetic polymorphisms and methotrexate outcomes are often inconsistent across populations. This narrative review synthesizes current evidence on ethnic variability in methotrexate pharmacogenetic associations among patients with rheumatoid arthritis. A structured literature search was conducted in PubMed/MEDLINE, Scopus, and Google Scholar up to January 2026, including human studies evaluating genetic polymorphisms in methotrexate-related pathways and reporting outcomes related to treatment effectiveness or toxicity. The available evidence is dominated by observational studies in populations of European and East Asian ancestry, with limited data from Southeast Asian cohorts. Polymorphisms in genes involved in methotrexate transport, intracellular activation, folate-dependent metabolism, and drug efflux demonstrate substantial interethnic differences in allele frequencies and reported clinical associations. Variants in folate metabolism genes are more consistently associated with methotrexate-related toxicity than with treatment effectiveness, whereas transporter and downstream pathway variants show population-dependent and heterogeneous associations with effectiveness. These inconsistencies are further influenced by methodological heterogeneity, including differences in outcome definitions, methotrexate dosing, folate supplementation, sample size, and adjustment for concomitant therapies. Overall, ethnic variability appears to be a key determinant of methotrexate pharmacogenetic associations in rheumatoid arthritis. Population-specific studies using standardized disease activity outcomes are required, particularly in underrepresented Southeast Asian populations especially Indonesia, to support equitable implementation of precision medicine strategies.]]>
